The present invention relates to a process for the stereoselective reduction of 6- and 8-keto phenanthrene derivatives including N-substituted derivatives, employing an alkaline solution of formamidinesulfinic acid to form the corresponding 6.beta.- and 8.beta.-hydroxy epimers thereof.
In recent years, there has been considerable interest in the development of narcotic antagonists capable of blocking the euphorigenic and addictive effects of narcotics. Exemplary of such compounds are cyclazocine,N-allylnoroxymorphone (naloxone), N-cyclopropylmethyl-noroxymorphone (naltrexone) and 3,14.beta.-dihydroxy-N-cyclobutulmethylmorphinan (butorphanol). Various derivatives in the morphine and morphinan series have heretofore been prepared which display combined narcotic antagonist-analgetic (agonist) properties. See, for example, U.S. Pat. Nos. 3,393,197; 3,332,950; 3,814,768; 3,819,635; and 3,896,226. Such derivatives having combined antagonist-agonist properties are very desirable as replacements for pure morphine in analgesic applications.
As a consequence of the species variation with respect to narcotic antagonist-agonist activity and relative potencies of various compounds previously investigated, there has also been considerable interest in delineating the role of biotransformation and metabolites in observed activity for morphine derivatives as well as determination of receptor stereospecificity. Accordingly, synthetic methods for the preparation of 6-keto reduction products of the morphine nucleus compounds have heretofore been described.
For example, processes for the synthesis of 6.alpha.-hydroxy epimers of N-substituted 14-hydroxydihydronormorphinones are known utilizing a hydride reduction to form the 6.alpha.-hydroxy derivatives of N-substituted 14-hydroxydihydronormorphines (I. J. Pachter and Z. Matossian, U.S. Pat. No. 3,393,197 [1968]). However, no process for the selective obtainment of 6.beta. epimeric morphine derivatives and especially from 6-keto morphine derivatives lacking the 14-hydroxy group have been described.
Although formamidinesulfinic acid has been used extensively for bleaching in the textile industry, few applications have been made of this reducing agent in preparative organic chemistry. Herz et al. have reported the reduction of certain 3- and 6-ketonic steroids (5.alpha.-chloestane 3-one) utilizing a strong alkaline solution of formamidinesulfinic acid as the reducing agent (Josef E. Herz and Lilia Albert de Marquez, J. Chem. Soc., 2633 [1973]). However, the authors also observed that regardless of whether the reducing agent was formamidinesulfinic acid, Na/alcohol or LiAlH.sub.4, reduction yielded the same ratio of isomers (3.beta.:3.alpha.) and that all three reagents favored equatorial alcohols (beta) in the chair conformation. The foregoing is clearly not the case with respect to 6-keto derivatives with the morphine skeleton, wherein it has been found that hydride reducing agents, for example, give predominantly 6.alpha.-OH products in which the hydroxy group is axial. Hydride reduction processes have resulted predominantly in the preparation of 6.alpha.-hydroxy morphine derivatives and such hydride reductions of compounds of this class have been generally totally ineffective in the stereoselective synthesis of 6.beta.-hydroxy compounds. See, E. J. Cone, Tetrahedron Letters, 2607 (1973), E. J. Cone, C. W. Gorodetzky and S. Y. Yeh, Pharmacologist 16, 225 (1974) and U. Weiss and S. J. Daum, J. Med. Chem., 8, 123 (1965). Also, with respect to the borohydride reduction of dihydrocodeinone, see Rull, Bull, Soc. Chim. France, 1337 (1962).